EP3571189B1 - Pyridine compounds as allosteric shp2 inhibitors - Google Patents

Pyridine compounds as allosteric shp2 inhibitors Download PDF

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Publication number
EP3571189B1
EP3571189B1 EP18701882.5A EP18701882A EP3571189B1 EP 3571189 B1 EP3571189 B1 EP 3571189B1 EP 18701882 A EP18701882 A EP 18701882A EP 3571189 B1 EP3571189 B1 EP 3571189B1
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Prior art keywords
alkyl
formula
optionally substituted
heterocycle
cycloalkyl
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EP18701882.5A
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German (de)
English (en)
French (fr)
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EP3571189A1 (en
Inventor
Adrian Gill
Naing Aay
Kevin MELLEM
Andreas BUCKL
Elena S. Koltun
Christopher Semko
Gert KISS
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Revolution Medicines Inc
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Revolution Medicines Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present disclosure relates to inhibitors of protein tyrosine phosphatase SHP2 useful in the treatment of diseases or disorders. Specifically, this disclosure is concerned with compounds and compositions inhibiting SHP2, methods of treating diseases associated with SHP2, and methods of synthesizing these compounds.
  • SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3- kinase-AKT pathways.
  • SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail.
  • the two SH2 domains control the subcellular localization and functional regulation of SHP2.
  • the molecule exists in an inactive, self-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.
  • SHP2 Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases.
  • the compounds of the present disclosure fulfill the need for small molecules to that inhibit the activity of SHP2.
  • the present disclosure relates to compounds capable of inhibiting the activity of SHP2.
  • the disclosure further provides a process for the preparation of compounds disclosed herein, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
  • the compounds according to the invention are of Formula I-Y1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein:
  • the compounds of the invention are of Formula I-Y6, or or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 5 and R 6 are -H.
  • the compounds of the invention are of Formula I-Y7, or or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 5 and R 6 are -H.
  • compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof) and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further comprise an excipient, diluent, or surfactant.
  • the pharmaceutical composition can be effective for treating a disease associated with SHP2 modulation in a subject in need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the disclosure not encompassed by the wording of the claims relates to one or more compounds disclosed herein (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use in treating or preventing a disease associated with SHP2 modulation.
  • compounds disclosed herein e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof
  • compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), and a pharmaceutically acceptable carrier, for use in treating of preventing a disease associated with SHP2 modulation.
  • compounds disclosed herein e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof
  • a pharmaceutically acceptable carrier for use in treating of preventing a disease associated with SHP2 modulation.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, for use for the treatment of a disease associated with SHP2 modulation.
  • the invention relates to a pharmaceutical composition of the invention for use for treating a disease associated with SHP2 modulation.
  • Another aspect of the disclosure not encompassed by the wording of the claims relates to one or more compounds disclosed herein (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • Another aspect of the disclosure not encompassed by the wording of the claims relates to pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • the medicament is used for treating or preventing a disease associated with SHP2 modulation.
  • the present disclosure also provides compounds and pharmaceutical compositions that are useful in inhibiting SHP2.
  • compounds of Formula I are described: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , and n are described as above.
  • compounds of the Formula II are described: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, R 1 , R 2 , R 3 , R 4 , Y 2 , and n are described as above.
  • compounds of the Formula III are described: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein A, R 1 , R 2 , R 3 , R 4 , Y 2 , and n are described as above.
  • an alkyl group that is optionally substituted may be a fully saturated alkyl chain (i.e. a pure hydrocarbon).
  • the same optionally substituted alkyl group may have substituents different from hydrogen. For instance, it can, at any point along the chain be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • the term “optionally substituted” may mean that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
  • aryl may refer to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, -H, -halogen, -O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl, -OC 2 -C 6 alkenyl, -OC 2 -C 6 alkynyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)C 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -OC(O)OCi-C 6 alkyl, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -S(O) 2 -C 1 -C 6 alkyl, -S(O)NHC 1 -C 6 alkyl, and -S(O)N(C 1 -C 6 alkyl
  • heteroaryl may mean a monovalent or multivalent monocyclic aromatic radical or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, S, P, and O, the remaining ring atoms being C.
  • Heteroaryl as herein defined also may mean a bicyclic heteroaromatic group wherein the heteroatom is selected from N, S, P, and O.
  • the term may also include multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below.
  • the term may also include multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1, 2, 3, 4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7, 8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system.
  • heteroaryls to form for example a naphthyridinyl such as 1,8-naphthyridinyl
  • heterocycles to form for example a 1, 2, 3, 4-tetrahydronaphth
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen).
  • the aromatic radical may be optionally substituted independently with one or more substituents described herein.
  • substituents include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, benzo[d]imidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, 1-methyl-1 H -indazolyl, pyrrolo[2,3-c
  • Alkyl may refer to a straight or branched chain saturated hydrocarbon.
  • C 1 -C 6 alkyl groups contain 1 to 6 carbon atoms. Examples of a C 1 -C 6 alkyl group may include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
  • alkenyl may mean an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl groups may have about 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, and i-butenyl.
  • a C 2 -C 6 alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.
  • alkynyl may mean an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups may have about 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups may include, but are not limited to, ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl.
  • a C 2 -C 6 alkynyl group is an alkynyl group containing between 2 and 6 carbon atoms.
  • cycloalkyl may mean monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms.
  • Examples of cycloalkyl groups may include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.
  • a C 3 -C 8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
  • a cycloalkyl group may be fused (e.g., decalin) or bridged (e.g., norbornane).
  • cycloalkenyl may mean monocyclic, non-aromatic unsaturated carbon rings containing 4-18 carbon atoms.
  • Examples of cycloalkenyl groups may include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl.
  • a C 4 -Cs cycloalkenyl is a cycloalkenyl group containing between 4 and 8 carbon atoms.
  • heterocyclyl or “heterocycloalkyl” or “heterocycle” may refer to monocyclic or polycyclic 3 to 24-membered rings containing carbon and heteroatoms selected from oxygen, phosphorus, nitrogen, and sulfur and wherein there are no delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms.
  • Heterocyclyl rings may include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.
  • a heteroycyclyl or heterocycloalkyl ring may also be fused or bridged, e.g., can be a bicyclic ring.
  • heterocyclyl or “heterocycloalkyl” or “heterocycle” may be a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-24 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)- or a ring sulfur atom may be optionally oxidised to form the S-oxides.
  • Heterocyclyl may be a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)- or a ring sulfur atom may be optionally oxidised to form S-oxide(s).
  • heterocyclyl may include thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydro thienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydro uracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyr
  • Spirocycle or “spirocyclic” may mean carbogenic bicyclic ring systems with both rings connected through a single atom.
  • the ring can be different in size and nature, or identical in size and nature. Examples may include, but are not limited to, spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P).
  • a C 5 -C 12 spirocycle is a spirocycle containing between 5 and 12 carbon atoms.
  • One or more of the carbon atoms can be substituted with a heteroatom.
  • spirocyclic heterocycle is understood to possibly mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl).
  • a spirocyclic heterocycle can contain between 5 and 12 atoms, at least one of which is a heteroatom selected from N, O, S and P.
  • compositions comprising an effective amount of one or more disclosed compounds and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier, diluent or excipient may include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • compositions may include pharmaceutically acceptable salts of the compounds disclosed herein.
  • pharmaceutically acceptable salts may include, e.g., watersoluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate,
  • “Pharmaceutically acceptable salt” also includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” may refer to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which may be formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulf
  • “Pharmaceutically acceptable base addition salt” may refer to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. For example, inorganic salts may include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • basic ion exchange resins such
  • tautomers may refer to a set of compounds that have the same number and type of atoms, but differ in bond connectivity and are in equilibrium with one another.
  • a "tautomer” is a single member of this set of compounds. Typically a single tautomer is drawn but it may be understood that this single structure may represent all possible tautomers that might exist. Examples include enol-ketone tautomerism. When a ketone is drawn it may be understood that both the enol and ketone forms are part of the disclosure.
  • prodrugs of the compounds described herein may mean a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
  • a prodrug may be a drug which is inactive in the body, but may be transformed in the body typically either during absorption or after absorption from the gastrointestinal tract into the active compound. The conversion of the prodrug into the active compound in the body may be done chemically or biologically (i.e., using an enzyme).
  • the disclosure may include solvates of the compounds described herein.
  • solvate may refer to a complex of variable stoichiometry formed by a solute and solvent.
  • solvents for the purpose of the disclosure may not interfere with the biological activity of the solute.
  • suitable solvents may include, but are not limited to, water, MeOH, EtOH, and AcOH.
  • Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates may include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the disclosure not encompassed by the wording of the claims may include isomers of the compounds described herein.
  • the term “isomer” may refer to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of the present disclosure may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • stereoisomers may refer to the set of compounds which have the same number and type of atoms and share the same bond connectivity between those atoms, but differ in three dimensional structure.
  • stereoisomer may refer to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer.
  • the present disclosure may embrace all geometric and positional isomers.
  • a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure.
  • the substituent may be in the E or Z configuration.
  • the cycloalkyl substituent may have a cis or trans configuration.
  • enantiomers may refer to a pair of stereoisomers which are non-superimposable mirror images of one another.
  • the term “enantiomer” may refer to a single member of this pair of stereoisomers.
  • the term “racemic” may refer to a 1:1 mixture of a pair of enantiomers.
  • the disclosure may include enantiomers of the compounds described herein. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
  • the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
  • the compounds may be the (S)-enantiomer.
  • the compounds may be the (R)-enantiomer.
  • the compounds may be the (+) or (-) enantiomers.
  • compounds and compositions of the disclosure may be enriched to provide predominantly one enantiomer of a compound described herein.
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5 or even 100 mol percent.
  • the compound described herein enriched in one enantiomer may be substantially free of the other enantiomer, wherein substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free may mean that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2 mol percent of the second enantiomer.
  • diastereomers may refer to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations may be considered to be diastereomers.
  • the term "diastereomer” may refer to any member of this set of compounds.
  • the synthetic route may produce a single diastereomer or a mixture of diastereomers.
  • the disclosure may include diastereomers of the compounds described herein.
  • the compounds and compositions of the disclosure may be enriched to provide predominantly one diastereomer of a compound disclosed herein.
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 99, 95, 96, 97, 98, 99, or even 100 mol percent.
  • the compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds.
  • An “isotopically” or “radio-labeled” compound may be a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • hydrogen atoms are replaced or substituted by one or more deuterium or tritium.
  • Certain isotopically labeled compounds of this disclosure for example, those incorporating a radioactive isotope, may be useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, i.e., 3 H, and carbon 14, i.e., 14 C may be particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Suitable isotopes that may be incorporated in compounds described herein include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl , 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 I.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N, can be useful in Positron Emission Topography (PET) studies.
  • PET Positron Emission Topography
  • an "effective amount" when used in connection with a compound may be an amount effective for treating or preventing a disease in a subject as described herein.
  • carrier may encompass carriers, excipients, and diluents and may mean a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • treating may refer to improving at least one symptom of the subject's disorder. Treating may include curing, improving, or at least partially ameliorating the disorder.
  • prevent or "preventing” with regard to a subject may refer to keeping a disease or disorder from afflicting the subject. Preventing may include prophylactic treatment. For instance, preventing can include administering to the subject one or more compounds disclosed herein before a subject is afflicted with a disease and the administration will keep the subject from being afflicted with the disease.
  • disorder is used in this disclosure and may be used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer may refer to either directly administering one or more disclosed compounds or a pharmaceutically acceptable salt of the one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject, or administering a prodrug derivative or analog of the one or more disclosed compounds or pharmaceutically acceptable salts of the one or more disclosed compounds or compositions to the subject, which may form an equivalent amount of active compound within the subject's body.
  • a “patient” or “subject” may be a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • the compound is of the Formula I-A: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • the compound is of the Formula I-B: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • the compound is of the Formula I-C: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-C, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-C, R 4 is -H. In one or more embodiments of Formula I-C, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-C, R 4 is -CF 2 OH or -CHFOH.
  • Y 2 is -(CR a 2 ) m -. In one or more embodiments of the compounds of Formula I-C, Y 2 is -NR a -. In one or more embodiments of the compounds of Formula I-C, Y 1 is -S-. In one or more embodiments of the compounds of Formula I-C, Y 1 is a direct bond.
  • A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula I-C, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-C, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-C, A is phenyl. In one or more embodiments of Formula I-C, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-C, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-C, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-C, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-C, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R a is -H.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula I-C, R 3 is an optionally substituted 3-to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula I-C, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula I-C, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • the compound is of the Formula II-A: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-A1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein: B forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the nitrogen atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • the compound is of the Formula II-A2: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-A3: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-B: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-B 1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein: B forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the carbon atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • the compound is of the Formula II-B2: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-B3: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-B4: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-B5: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-B6: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-C: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein: B forms a 3- to 12-membered monocyclic or polycyclic heterocycle, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2
  • the compound is of the Formula II-C1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-D: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein: B forms a 3- to 12-membered monocyclic or polycyclic heterocycle, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • the compound is of the Formula II-D1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-E: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-F: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula II-G: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein R 2 is an aryl or heteroaryl.
  • the compound is of the Formula II-H: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula II-H, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula II-H, R 4 is -H. In one or more embodiments of Formula II-H, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula II-H, R 4 is -CF 2 OH or -CHFOH.
  • Y 2 is -(CR a 2 ) m -. In one or more embodiments of the compounds of Formula II-H, Y 2 is -NR a -.
  • A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula II-H, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula II-H, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula II-H, A is phenyl. In one or more embodiments of Formula II-H, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula II-H, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula II-H, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula II-H, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula II-H, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R a is -H.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula II-H, R 3 is an optionally substituted 3-to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula II-H, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula II-H, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • the compound is of the Formula III-A: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula III-A1:
  • the compound is of the Formula III-A2: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula III-A3: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • the compound is of the Formula III-B: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula III-B, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more - OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula III-B, R 4 is -H. In one or more embodiments of Formula III-B, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula III-B, R 4 is -CF 2 OH or -CHFOH.
  • Y 2 is -(CR a 2 ) m -. In one or more embodiments of the compounds of Formula III-B, Y 2 is -NR a -.
  • A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula III-B, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula III-B, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula III-B, A is phenyl. In one or more embodiments of Formula III-B, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula III-B, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula III-B, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula III-B, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula III-B, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R a is -H.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula III-B, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula III-B, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula III-B, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • the compound is of the Formula I-X1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-X1, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-X1, R 4 is -H. In one or more embodiments of Formula I-X1, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-X1, R 4 is -CF 2 OH or -CHFOH.
  • Y 2 is -(CR a 2 ) m -. In one or more embodiments of the compounds of Formula I-X1, Y 2 is -NR a -. In one or more embodiments of the compounds of Formula I-X1, Y 1 is -S-. In one or more embodiments of the compounds of Formula I-X1, Y 1 is a direct bond.
  • A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula I-X1, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-X1, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-X1, A is phenyl. In one or more embodiments of Formula I-X1, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-X1, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-X1, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-X1, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-X1, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R a is -H.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula I-X1, R 3 is an optionally substituted 3-to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula I-X1, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula I-X1, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , or -OH.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • the compound is of the Formula I-Y1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y1, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y1, R 4 is -H. In one or more embodiments of Formula I-Y1, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y1, R 4 is -CF 2 OH or -CHFOH.
  • Y 2 is -(CR a 2 ) m -. In one or more embodiments of the compounds of Formula I-Y1, Y 2 is -NR a -. In one or more embodiments of the compounds of Formula I-Y1, Y 1 is -S-. In one or more embodiments of the compounds of Formula I-Y1, Y 1 is a direct bond.
  • A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula I-Y1, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-Y1, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y1, A is phenyl. In one or more embodiments of Formula I-Y1, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y1, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y1, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y1, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-Y1, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R a is -H.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula I-Y1, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula I-Y1, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula I-Y1, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , - CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , - CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • the compound is of the Formula I-Y2: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-Y2, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y2, A is phenyl. In one or more embodiments of Formula I-Y2, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y2, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y2, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y2, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-Y2, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y2, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y2, R 4 is -H. In one or more embodiments of Formula I-Y2, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y2, R 4 is -CF 2 OH or -CHFOH.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • the compound is of the Formula I-Y3: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein: B forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the nitrogen atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , -CF 3 , -CHF 2 , or -CH 2 F. In certain such embodiments, the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-Y3, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y3, A is phenyl. In one or more embodiments of Formula I-Y3, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y3, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y3, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y3, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-Y3, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y3, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y3, R 4 is -H. In one or more embodiments of Formula I-Y3, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y3, R 4 is -CF 2 OH or -CHFOH.
  • the compound is of the Formula I-Y4: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof.
  • A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-Y4, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y4, A is phenyl. In one or more embodiments of Formula I-Y4, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y4, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y4, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y4, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-Y4, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y4, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y4, R 4 is -H. In one or more embodiments of Formula I-Y4, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y4, R 4 is -CF 2 OH or -CHFOH.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , - CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , - CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • the compound is of the Formula I-Y5: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein: B forms a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle along with the nitrogen atom to which it is attached, wherein the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , -CF 3 , -CHF 2 , or -CH 2 F. In certain such embodiments, the heterocycle or spiroheterocycle is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-Y5, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y5, A is phenyl. In one or more embodiments of Formula I-Y5, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y5, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y5, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y5, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-Y5, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y5, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y5, R 4 is -H. In one or more embodiments of Formula I-Y5, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y5, R 4 is -CF 2 OH or -CHFOH.
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y2 or I-Y4 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the present disclosure provides a compound of Formula I-Y3 or I-Y5 having one, two, three, four, or more of the following features:
  • the compound is of Formula I-Y6: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • the compounds according to the invention are of Formula I-Y6, or or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 5 and R 6 are -H.
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y6, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more - OH. In one or more embodiments of Formula I-Y6, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y6, R 4 is -H. In one or more embodiments of Formula I-Y6, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y6, R 4 is -CF 2 OH or -CHFOH.
  • R 2 is -OH. In one or more embodiments of Formula I-Y6, R 2 is -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • Formula I-Y6 A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y6, A is phenyl. In one or more embodiments of Formula I-Y6, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y6, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y6, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . According to the invention, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y6, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • the compound is of Formula I-Y7: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • the compounds according to the invention are of Formula I-Y7, or or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein R 5 and R 6 are -H.
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Y7, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more -OH. In one or more embodiments of Formula I-Y7, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Y7, R 4 is -H. In one or more embodiments of Formula I-Y7, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Y7, R 4 is -CF 2 OH or -CHFOH.
  • R 2 is -OH. In one or more embodiments of Formula I-Y7, R 2 is -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Y7, A is phenyl. In one or more embodiments of Formula I-Y7, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Y7, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Y7, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . According to the invention, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Y7, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • the compound is of the Formula I-Z1: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, wherein:
  • R 4 is -C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I-Z1, R 4 is -C 1 -C 6 alkyl, which is substituted with one or more - OH. In certain such embodiments, R 4 is -CH 2 -OH. In one or more embodiments of Formula I-Z1, R 4 is -H. In one or more embodiments of Formula I-Z1, R 4 is -C 1 -C 6 haloalkyl or -C 1 -C 6 hydroxyalkyl. In one or more embodiments of Formula I-Z1, R 4 is -CF 2 OH or -CHFOH.
  • Y 2 is -(CR a 2 ) m -. In one or more embodiments of the compounds of Formula I-Z1, Y 2 is -NR a -. In one or more embodiments of the compounds of Formula I-Z1, Y 1 is -S-. In one or more embodiments of the compounds of Formula I-Z1, Y 1 is a direct bond.
  • A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula I-Z1, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I-Z1, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I-Z1, A is phenyl. In one or more embodiments of Formula I-Z1, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula I-Z1, A is pyridinyl.
  • n is independently, at each occurrence, 0, 1, 2, or 3. In one or more embodiments of Formula I-Z1, n is independently, at each occurrence, 1 or 2.
  • R 1 is independently, at each occurrence, -H, halogen or -NR 5 R 6 . In certain such embodiments, R 5 and R 6 are both -H. In one or more embodiments of Formula I-Z1, R 1 is independently, at each occurrence, -H, methyl, fluoro, chloro, or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I-Z1, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, R 2 is methyl.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered monocyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or - CH 2 F.
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 3- to 12-membered polycyclic heterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , - CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 5- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, - OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , -CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -NH 2 , -OH, -CF 3 , -CHF 2 , or -CH 2 F.
  • R 3 and R a together with the atoms to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl or -NH 2 .
  • R 3 and R a together with the atom to which they are attached combine to form a 10- to 12-membered spiroheterocycle, which is optionally substituted with one or more -C 1 -C 6 alkyl, -OH, -NH 2 , heteroaryl, heterocyclyl, -(CH 2 ) n NH 2 , -COOR b , -CONHR b , - CONH(CH 2 ) n COOR b , -NHCOOR b , -CF 3 , -CHF 2 , or -CH 2 F.
  • R a is -H.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula I-Z1, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula I-Z1, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula I-Z1, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, A is monocyclic or polycyclic heteroaryl.
  • A is phenyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, A is pyridinyl.
  • Y 1 is -S-. In one or more embodiments of Formula I, I-X, I-Y, or I-Z, Y 1 is a direct bond.
  • Y 2 is -NR a -. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, Y 2 is -(CR a 2 ) m -. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, Y 2 is -C(O)-. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, Y 2 is -C(R a ) 2 NH- or -(CR a 2 ) m O-.
  • Y 2 is -C(O)N(R a )-, - N(R a )C(O)-, -S(O) 2 N(R a )-, -N(R a )S(O) 2 -, -N(R a )C(S)-, or -C(S)N(R a )-.
  • Y 2 is -N(R a )C(O)N(R a )-, -N(R a )C(S)N(R a )-, -OC(O)N(R a )-, -N(R a )C(O)O-, or -C(O)N(R a )O-.
  • Y 2 is -C(O)O-, -OC(O)-, or -OC(O)O-.
  • R 1 is independently, at each occurrence, selected from -H, optionally substituted -C 1 -C 6 alkyl, halogen, -OH, -CN, and -NR 5 R 6 . In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 1 is independently, at each occurrence, selected from -H, optionally substituted -C 1 -C 6 alkyl, halogen, -OH, and -NR 5 R 6 .
  • R 1 is independently, at each occurrence, selected from -H, optionally substituted -C 1 -C 6 alkyl, halogen, and -NR 5 R 6 . In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 1 is independently, at each occurrence, selected from -H, methyl, fluoro, chloro, bromo, and -NH 2 .
  • R 1 is independently, at each occurrence, selected from -H, methyl, fluoro, chloro, and -NH 2 . In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 1 is -H. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 1 is independently, at each occurrence, -H or halogen. In certain such embodiments, the halogen is chloro. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 1 is independently, at each occurrence, -H or -NH 2 .
  • R 2 is -OH. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is an optionally substituted -C 1 -C 6 alkyl. In certain such embodiments, the -C 1 -C 6 alkyl is methyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is -CN. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is an optionally substituted -C 2 -C 6 alkenyl.
  • R 2 is an optionally substituted -C 4 -Cscycloalkenyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is an optionally substituted -C 2 -C 6 alkynyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is optionally substituted -C 3 -C 8 cycloalkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is aryl.
  • R 2 is an optionally substituted heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is an optionally substituted heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O.
  • R a is -H. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R a is -OH. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R a is an optionally substituted -C 3 -C 8 cycloalkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R a is an optionally substituted -C 1 -C 6 alkyl.
  • R b is H. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R b is an optionally substituted C 1 -C 6 alkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R b is an optionally substituted -C 3 -C 8 cycloalkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R b is an optionally substituted -C 2 -C 6 alkenyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R b is an optionally substituted heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O.
  • R 3 is an optionally substituted -C 1 -C 6 alkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 3 is an optionally substituted 3- to 12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 3 is an optionally substituted 3- to 12-membered monocyclic heterocycle. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 3 is an optionally substituted 5- to 12-membered polycyclic heterocycle.
  • R 4 is -H. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 4 is -C 1 -C 6 alkyl. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 4 is -C 1 -C 6 alkyl substituted with one or more -OH, -NH 2 , halogen, or oxo. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 4 is -C 1 -C 6 alkyl substituted with -OH.
  • R 4 is -CH 2 OH. In one or more embodiments of Formula I, II, III, I-X, I-Y, or I-Z, R 4 is -CF 2 OH or -CHFOH,
  • R 3 and R a together with the atom to which they are attached combine to form an optionally substituted 3- to 12-membered monocyclic heterocycle.
  • R 3 and R a together with the atoms to which they are attached combine to form an optionally substituted 3- to 12-membered polycyclic heterocycle.
  • R 3 and R a together with the atoms to which they are attached combine to form an optionally substituted 5- to 12-membered spiroheterocycle.
  • R a and R 4 together with the atom to which they are attached combine to form an optionally substituted monocyclic or polycyclic 3- to 12-membered cycloalkyl.
  • R a and R 4 together with the atom to which they are attached combine to form an optionally substituted monocyclic or polycyclic 3- to 12-membered heterocycle.
  • R 2 is -C 1 -C 6 alkyl and R 4 is H. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is -C 1 -C 6 alkyl and R 4 is -C 1 -C 6 alkyl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is -C 1 -C 6 alkyl and R 4 is -C 1 -C 6 alkyl substituted with one or more -OH, -NH 2 , halogen, or oxo.
  • R 2 is -C 1 -C 6 alkyl and R 4 is -C 1 -C 6 alkyl substituted with -OH. In certain such embodiments, R 4 is -CH 2 OH.
  • R 2 is -OH and R 4 is H. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is -OH and R 4 is -C 1 -C 6 alkyl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, R 2 is -OH and R 4 is -C 1 -C 6 alkyl substituted with one or more -OH, -NH 2 , halogen, or oxo.
  • R 2 is -OH and R 4 is -C 1 -C 6 alkyl substituted with -OH. In certain such embodiments, R 4 is -CH 2 OH.
  • Y 1 is S and A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl.
  • Y 1 is S and A is a monocyclic or polycyclic heterocycloalkyl.
  • Y 1 is S and A is monocyclic or polycyclic aryl.
  • Y 1 is S and A is monocyclic or polycyclic heteroaryl.
  • Y 1 is S and A is phenyl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, Y 1 is S and A is pyridinyl.
  • Y 1 is a direct bond and A is a 5- to 12-membered monocyclic or polycyclic cycloalkyl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, Y 1 is a direct bond and A is a monocyclic or polycyclic heterocycloalkyl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, Y 1 is a direct bond and A is monocyclic or polycyclic aryl.
  • Y 1 is a direct bond and A is monocyclic or polycyclic heteroaryl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, Y 1 is a direct bond and A is phenyl. In certain instances of Formula I, II, III, I-X, I-Y, or I-Z, Y 1 is a direct bond and A is pyridinyl.
  • a compound of the invention can be selected from: and pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers of any of the foregoing.
  • a compound of the invention can be selected from: Example 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 and 19
  • the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.
  • the compounds of any of the formulae described herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes and examples.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis ( T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," Third edition, Wiley, New York 1999 ). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of the present disclosure.
  • the present disclosure may include both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, " Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994 ).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods include but are not limited to those methods described below.
  • a general synthesis of 5-amino-2-thioaryl-(or thioheteroaryl)-3-methylpyridines is outlined in Scheme 1.
  • 2,5-dibromo-3-methylpyridine can be coupled to a substituted aryl- or heteroaryl 1-thiol in the presence of a copper catalyst (e.g., CuI).
  • the resulting thioether can then be coupled to a substituted primary or secondary amine to give a 5-amino-2-thioaryl-(or thioheteroaryl)-3-methylpyridines. Additional deprotection and/or functionalization steps can be required to produce the final compound.
  • a general synthesis of 5-amino-2-aryl-(or heteroaryl)-3-methylpyridines is outlined in Scheme 2.
  • 2,5-dibromo-3-methylpyridine can be coupled to a substituted aryl- or heteroaryl boronic acid in the presence of a palladium catalyst (e.g., Pd(dppf)Cl 2 ).
  • the resulting biaryl intermediate can then be coupled to a substituted primary or secondary amine to give 5-amino-2-aryl-(or heteroaryl)-3-methylpyridines. Additional deprotection and/or functionalization steps can be required to produce the final compound.
  • a general synthesis of 5-amino-2-thioaryl-(or thioheteroaryl)-6-methylhydroxy-3-methylpyridines is outlined in Scheme 3.
  • 5-Amino-2-thioaryl-(or thioheteroaryl)-3-methylpyridines can be brominated followed by cabonylation.
  • the resulting ester intermediate can be subsequently reduced to produce 5-amino-2-thioaryl-(orthioheteroaryl)-6-methylhydroxy-3-methylpyridines. Additional deprotection and/or functionalization steps can be required to produce the final compound.
  • Another aspect of the disclosure not encompassed by the wording of the claims relates to methods of treating a disease associated with SHP2 modulation in a subject in need thereof.
  • the methods may involve administering to a patient in need of treatment for diseases or disorders associated with SHP2 modulation an effective amount of one or more compounds of the present disclosure (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), or of one or more pharmaceutical compositions of the present disclosure.
  • the disease can be, but is not limited to Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
  • SHP2 is an important downstream signaling molecule for a variety of receptor tyrosine kinases, including the receptors of platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth factor (EGF-R).
  • PDGF-R platelet-derived growth factor
  • FGF-R fibroblast growth factor
  • EGF-R epidermal growth factor
  • SHP2 is also an important downstream signaling molecule for the activation of the mitogen activated protein (MAP) kinase pathway which can lead to cell transformation, a prerequisite for the development of cancer.
  • MAP mitogen activated protein
  • SHP2 significantly inhibited cell growth of lung cancer cell lines with SHP2 mutation or EML4/ALK translocations as well as EGFR amplified breast cancers and esophageal cancers.
  • SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma.
  • SHP2 plays a role in transducing signals originating from immune checkpoint molecules, including but not limited to programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • CTL-4 cytotoxic T-lymphocyte-associated protein 4
  • modulation of SHP2 function can lead to immune activation, specifically anti-cancer immune responses.
  • the present disclosure relates to compounds or compositions disclosed herein that are capable of modulating the activity of (e.g., inhibiting) SHP2.
  • the present disclosure also relates to the therapeutic use of such compounds and compositions.
  • One or more disclosed compounds or compositions can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • SHP2 is inhibited after treatment with less than 1000 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with 10 nM to 100 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with less than 10 nM of a compound of the disclosure.
  • One or more disclosed compounds or compositions can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • SHP2 is inhibited after treatment with less than 1000 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 1 nM to about 10 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 100 nM to about 10 ⁇ M of a compound of the disclosure.
  • Another aspect of the present disclosure not encompassed by the wording of the claims relates to a one or more compounds of the present disclosure (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), or one or more compositions of the present disclosure for use in treating or preventing a disease associated with SHP2 modulation.
  • the invention relates to a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, for use for the treatment of a disease associated with SHP2 modulation.
  • the invention relates to a pharmaceutical composition of the invention for use for treating a disease associated with SHP2 modulation.
  • the disease is Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
  • SHP2 is an important downstream signaling molecule for a variety of receptor tyrosine kinases, including the receptors of platelet-derived growth factor (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth factor (EGF-R).
  • PDGF-R platelet-derived growth factor
  • FGF-R fibroblast growth factor
  • EGF-R epidermal growth factor
  • SHP2 is also an important downstream signaling molecule for the activation of the mitogen activated protein (MAP) kinase pathway which can lead to cell transformation, a prerequisite for the development of cancer. Knock-down of SHP2 significantly inhibited cell growth of lung cancer cell lines with SHP2 mutation or EML4/ALK translocations as well as EGFR amplified breast cancers and esophageal cancers. SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma.
  • MAP mitogen activated protein
  • the present disclosure relates to one or more compounds of the present disclosure (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • the medicament is used for treating or preventing a disease associated with SHP2 modulation.
  • the present disclosure relates to one or more compositions comprising one or more compounds of the present disclosure (e.g., compounds of Formula I, II, III, I-X, I-Y, or I-Z, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof), for use as a medicament.
  • the medicament is used for treating or preventing a disease associated with SHP2 modulation.
  • compositions comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier.
  • the invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant.
  • compositions of the disclosure can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of one or more of the disclosed compounds by weight or volume.
  • Administration of the disclosed compounds and compositions may be accomplished via any mode of administration for therapeutic agents. These modes may include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions may include tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • one or more of the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • One or more disclosed compounds or compositions can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • One or more disclosed compounds or compositions can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described for instance in U.S. Pat. No. 5,262,564 , the contents of which are hereby incorporated by reference.
  • One or more disclosed compounds or compositions can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the one or more disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • one or more disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • One or more disclosed compounds or compositions can be delivered by parental administration.
  • Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • the dosage regimen utilizing one or more disclosed compounds or compositions may be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the disclosed compounds when used for the indicated effects, may range from about 0.5 mg to about 5000 mg of the disclosed compounds as needed to treat the condition.
  • Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compounds, or, in a range of from one amount to another amount in the list of doses.
  • the compositions are in the form of a tablet that can be scored.
  • the effective daily dose of one or more compounds or compositions of this disclosure may be administered as one, two, three, four, five, six, or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the one or more compounds or compositions of this disclosure, or mixtures thereof may be administered two or three times daily.
  • the one or more compounds or compositions of this disclosure will be administered once daily.
  • one or more compounds or compositions described herein may be used alone or together or conjointly administered, or used in combination, with another type of therapeutic agent.
  • Conjoint administration or used in combination may refer to any form of administration of two or more different therapeutic compounds or compositions such that the second compound or composition is administered while the previously administered therapeutic compound or composition is still effective in the body.
  • the different therapeutic compounds or compositions can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment.
  • the different therapeutic compounds or compositions can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds or compositions.
  • this disclosure not encompassed by the wording of the claims also provides a pharmaceutical package or kit comprising one or more containers filled with at least one compound or composition of this disclosure.
  • a pharmaceutical package or kit comprising one or more containers filled with at least one compound or composition of this disclosure.
  • Optionally associated with such a container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects (a) approval by the agency of manufacture, use or sale for human administration, (b) directions for use, or both.
  • the kit comprises at least two containers, at least one of which contains at least one compound or composition of this disclosure.
  • the kit contains at least two containers, and each of the at least two containers contains at least one compound or composition of this disclosure.
  • the kit includes additional materials to facilitate delivery of the subject compounds and compositions.
  • the kit may include one or more of a catheter, tubing, infusion bag, syringe, and the like.
  • the compounds and compositions may be packaged in a lyophilized form, and the kit includes at least two containers: a container comprising the lyophilized compounds or compositions and a container comprising a suitable amount of water, buffer, or other liquid suitable for reconstituting the lyophilized material.
  • Embodiment I As follows:
  • Embodiment II A compound of Formula I-Y1: or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, wherein:
  • N-[(4R)-8-[5-benzyloxy-6-(2,3-dichlorophenyl)-3-pyridyl]-8-azaspiro[4.5]decan-4-yl]-2-methyl-propane-2-sulfinamide (1.15 g, 1.96 mmol) in DCM (15 mL) was added NBS (1.05 g, 5.88 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by the addition of saturated NaHSOs (5 mL).
  • Example 18 Synthesis of 5-[( 3S , 4S )-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-2-(2,3-dichlorophenyl)-6-(hydroxymethyl)pyridin-3-ol.
  • reaction mixture was stirred at 85 °C for 2 hrs.
  • the reaction mixture was filtered and the filtrate was purified by reversed-phase column chromatography to afford [5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-methoxycarbonyl-3-pyridyl]boronic acid (0.4 g, 43 % yield) as a white solid.
  • SHP is allosterically activated through binding of bis-tyrosyl-phosphorylated peptides to its Src Homology 2 (SH2) domains.
  • SH2 Src Homology 2
  • the latter activation step leads to the release of the auto-inhibitory interface of SHP2, which in turn renders the SHP2 protein tyrosine phosphatase (PTP) active and available for substrate recognition and reaction catalysis.
  • PTP protein tyrosine phosphatase
  • the catalytic activity of SHP2 was monitored using the surrogate substrate DiFMUP in a prompt fluorescence assay format.
  • the phosphatase reactions were performed at room temperature in 96-well black polystyrene plate, flat bottom, non-binding surface (Corning, Cat # 3650) using a final reaction volume of 100 ⁇ L and the following assay buffer conditions: 50 mM HEPES, pH 7.2, 100 mM NaCl, 0.5 mM EDTA, 0.05% P-20, 1 mM DTT.
  • SHP2 The inhibition of SHP2 by compounds of the disclosure (concentrations varying from 0.00005-10 ⁇ M) was monitored using an assay in which 0.2 nM of SHP2 was incubated with 0.5 ⁇ M of Activating Peptide 1 (sequence: H 2 N-LN(pY)IDLDLV(dPEG8)LST (pY)ASINFQK-amide) or Activating Peptide 2 (sequence: H 2 N-LN(pY)AQLWHA(dPEG8) LTI(pY)ATIRRF-amide).
  • the surrogate substrate DiFMUP (Invitrogen, Cat # D6567) was added to the reaction and activity was determined by a kinetic read using a microplate reader (Envision, Perkin-Elmer or Spectramax M5, Molecular Devices). The excitation and emission wavelengths were 340 nm and 450 nm, respectively. Initial rates were determined from a linear fit of the data, and the inhibitor dose response curves were analyzed using normalized IC 50 regression curve fitting with control based normalization.
  • compounds of the disclosure tested in the assay described above demonstrated an activity of less than 1000 nM. In some embodiments, compounds of the disclosure tested in the assay described above demonstrated an activity of about 10 nM to about 100 nM. In some embodiments, compounds of the disclosure tested in the assay described above demonstrated an activity of 10 nM to 100 nM. In some embodiments, compounds of the disclosure tested in the assay described above demonstrated an activity of less than 10 nM.
  • One or more disclosed compounds or compositions can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • SHP2 is inhibited after treatment with less than 1000 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 1 nM to about 10 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the disclosure. In some embodiments, SHP2 is inhibited after treatment with about 100 nM to about 10 ⁇ M of a compound of the disclosure.

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